Processes for the manufacturing of 3-hydroxy-n,1,6-trialkyl-4-OXO-1,4-dihydropyridine-2-carboxamide

ABSTRACT

The present invention relates to a novel process for the preparation of 3-hydroxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide of formula I:                    
     The method comprises of the TEMPO oxidation of a primary alcohol of 3-O-protected-2-hydroxymethyl-6-alkyl-4H-pyran-4-one of formula III to 3-O-protected-4-alkyl-4-oxo-4H-pyran-2-carboxylic acid of formula II. Reaction of compound of formula II with methylamine and 1,1-carbonyidiimidazole in an inert solvent affords 3-O-protected-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide, which is deprotected to give of 3-hydroxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide of formula I.

This application is a division of Application No. 9/985,269, filed Nov.2, 2001, the entire content of which is hereby incorporated by referencein this application.

FIELD OF INVENTION

This invention relates to the novel process for the manufacturing of3-hydroxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide offormula I,

intermediates of formulae II and III useful in the manufacturing of such4-oxo-1,4-dihydropyridine-2-carboxamide, and novel process for themanufacturing of the intermediates used.

wherein:

R¹, R², R³, R⁶ are independently, hydrogen, lower alkyl,

R⁴ is lower alkyl, hydrogen, lower alkoxy,

R⁵ is hydrogen, an alcohol protective group, benzyl and a benzyl groupoptionally substituted with nitro, lower alkyl and lower alkoxy.

Lower alkyl groups include straight and branched chain hydrocarbonradicals from 1 to 6 carbon atoms.

Lower alkoxy groups include -O-[lower alkyl] wherein lower alkyl isdefined above.

Alcohol protective group commonly used includes those which are wellknown in the art, for example, benzyl, 2,6-dimethylbenzyl,4-methoxybenzyl, o-nitrobenzyl, 2,6-dichlorobenzyl, 3,4-dichlorobenzyl,4-(dimethylamino) carbonylbenzyl, 4-methylsulfinylbenzyl,9-anthrylmethyl, 4-picolyl, heptafluoro-p-tolyl, tetrafluoro-4-pyridyl,formate, acetate, benzoate, benzyloxycarbonyl, methoxycarbonyl,t-butyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, methoxymethyl,benzyloxymethyl, methoxyethoxymethyl, t-butyl.

According to further aspects of this invention, there are providedmethods for the conversion compounds of formula II to3-benzyloxy-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide, and3-benzyloxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide,3-hydroxy-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide and3-hydroxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide offormula I.

A third aspect of this invention relates to a process of reacting anacid of formula II with 1,1′-carbonyldiimidazole, alkylamine and aninert solvent to give a compound of formula I.

A fourth aspect of this invention concerns the process of oxidizing acompound of formula III with TEMPO, sodium hypochlorite solution, sodiumbicarbonate (baking soda) and potassium bromide to give a compound offormula II.

BACKGROUND OF INVENTION

This invention relates to certain3-hydroxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide offormula I as orally active iron chelators. Members of the3-hydroxy-4-oxo-1,4-dihydropyridine class are well known for theirability to chelate iron in physiological environment and these have beenreported as useful in the treating iron related disorders such asthalassaemia and anemia, see U.S. Pat. No. 4,840,958, U.S. Pat. No.5,480,894, U.S. Pat. No. 5,688,815, J. Med. Chem. 1999, 42(23),4818-4823.

3-Hydroxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide arebidentate iron I chelators with potential for oral administration, seeBioorganic & Medicinal Chemistry 9 (2001), 563-567. A patent applicationhas been published emphasizing the pharmacological properties of thisclass of compound, see WO98/54318. Compounds of formula I have beentested in iron mobilization efficacy assay in rat via the mode of oraladministration. The results are reported in Table 3 of WO98/54318.Compounds of formula I are chelators possessing high pFe³⁺ values andshow great promise in their ability to remove iron under in-vivoconditions.

3-Hydroxy-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide hasbeen prepared by the method, described in examples 45 to 48, 53, and 58of WO98/54318. Allomaltol (1) is converted to2-(1-hydroxymethyl)-6-methylpyromeconic acid (2) according to theprocedure described in FR1516463. The2-(1-hydroxymethyl)-6-methylpyromeconic acid (2) is reacted with benzylbromide in sodium hydroxide in a 10:1 mixture of methanol and water togive the 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (3) whichis then oxidized with diemthyl sulfoxide and sulfur trioxide.pyridinecomplex to give 2-formyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (4).Oxidation of the 2-formyl derivative with sulfamic acid and sodiumhypochlorite in acetone and water affords2-carboxyl-3-benzyloxy-6-methyl-pyran4(1H)-one (5). The 2-carboxylderivative is reacted with dicyclohexyldiimide and 2-mercaptothiazolineand 4-dimethylaminopyridine to give the3-(2-carbonyl-3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-1,3-thiazolidine-2-thione(6) which is reacted with methylamine in tetrahydrofuran to give3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide (7).The 3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide(7) is converted to1,6-dimethyl-3-benzyloxy4(1H)-pyridinone-2-carboxy-)N-methyl)-amide (8)with methylamine in alcohol. The 3-benzyloxy derivative was deprotectedwith hydrogenation using Pd/C in dimethylformamide as illustrated inScheme 1 to give1,6-dimethyl-3-hydroxy4(1H)-pyridinone-2-carboxy-)N-methyl)-amide (9):

Scheme 1: a. HCHO, NaOH; b. PhCH₂Br, NaOH, MeOH, H₂O; c. DMSO,SO₃.pyridine, CHCl₃, Et₃N; d. sulfamic acid, NaClO₂, acetone, water; e.DCC, CH₂Cl₂, 2-mercaptothiazoline; f. MeNH₂, THF; g. MeNH₂, MeOH; h. H₂,Pd/C, EtOH.

The IUPAC name of the chemicals shown in Scheme 1 is further clarifiedbelow:

Compound (3): 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran4(1H)-one has analternate IUPAC name3-(benzyloxy)-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one.

Compound (5): 2-carboxyl-3-benzyloxy-6-methyl-pyran-4(1H)-one has analternate IUPAC name 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylicacid.

Compound (8):1,6-dimethyl-3-benzyloxy4(1H)-pyridinone-2-carboxy-)N-methyl)-amide hasan alternate IUPAC name:3-(benzyloxy)-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide.

Compound (9):1,6-dimethyl-3-hydroxy4(1H)-pyridinone-2-carboxy-)N-methyl)-amide has analternate IUPAC Name:3-hydroxy-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide.

When compared to the above process, the applicant's invention introducesa number of advantages over the existing process:

1. It affords1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-)N-methyl)-amide inconsiderably higher yields than existing procedures.

2. It is amenable to industrial scale production since3-hydroxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide can bemade in less process steps from economically, commercially availablereagents.

3. It avoids the use of oxidizing agent such as DMSO, sulfurtrioxide.pyridine and the need for column chromatography using diethylether and the isolation of the intermediate2-formyl-3-benzyloxy-6-methyl-pyran-4(1H)-one. It avoids the generationof large amount of industrial waste and the execution of the synthesisin two distinct separate steps for the conversion of2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one to3-benzyloxy-2-carboxy-6-methyl-pyran-4(1H)-one. The conversion of2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one to3-benzyloxy-2-carboxy-6-methyl-pyran-4(1H)-one is achieved in one singleprocess step using baking soda (sodium bicarbonate), sodium hypochloritesolution, and TEMPO. The labour cost is significantly reduced because ofthe short reaction time and ease of work-up.

4. It avoids the isolation and purification of intermediates such as3-hydroxy-2-hydroxymethyl-6-methyl-pyran-4(1H)-one,3-benzyloxy-2-formyl-6-methyl-pyran-4(1H)-one,3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide. Theisolation of these intermediates involve extra process step, labourcost, and waste disposal, thereby rendering the process more expensive.

5. It eliminates the use of intermediate3-(2-carbonyl-3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-1,3-thiazolidine-2-thione.It does not use 2-mercaptothiazoline which requires its removal aschemical waste in the later step.

6. It avoids the use of reagent dicyclohexyldiimide and the generationof dicyclohexylurea waste that are skin irritant.

7. It does not require three distinct steps for the conversion of2-carboxyl-3-benzyloxy-6-methyl-pyran-4(1H)-one to3-benzyloxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide. Theconversion is achieved in one single process step. The labour cost issignificantly reduced because of the short reaction time and ease ofwork-up.

8. An efficient process is described for the large scale manufacturingof 2-chlorokojic acid, a key intermediate for the synthesis ofallomaltol. The existing literature process is not amenable to largescale synthesis.

Therefore, one object of the invention is to provide novel process forthe production of1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-)N-methyl)-amide and1,6-dimethyl-3-hydroxy-4(1H)-pyridinone-2-carboxy-)N-methyl)-amide fromreadily available, inexpensive and relatively safe starting material.Other objects of this invention can be recognized by those skills in theart from the summary of invention and detailed description ofembodiments thereof.

SUMMARY OF INVENTION

According to one aspect of the invention, a process is provided to makethe compound of formula I which comprises of the step of oxidation ofIII to the acid of formula II in a single process step as shown inscheme 2. The oxidants are TEMPO, baking soda, sodium hypochlorite andpotassium bromide. Compound II is then reacted with1,1′-carbonyldiimidazole and methylamine in an inert solvent to give acompound of formula I in a single process step. The alcohol protectivegroup R⁵ can be deprotected to give a compound of formula I wherein R⁵is hydrogen. The compound of formula III is in turn prepared from thecompound of formula IV in a single process step.

DETAILED DESCRIPTION OF INVENTION

Allomaltol (compound of formula IV wherein R¹=Me, R⁴=H, R⁵=H) is reactedwith formaldehyde in a sodium hydroxide solution in methanol and waterfor a period of 6 to 16 hrs. Benzyl chloride was added and the reactionwas heated to reflux for 4 to 12 hours, preferably 6 hours. Thebenzylated alcohol (compound of formula III wherein R¹=Me, R⁴=H,R⁵=CH₂Ph) is isolated by traditional means. This procedure eliminatesthe use of a more expensive reagent benzyl bromide and the need toisolate the diol intermediate3-hydroxy-2-hydroxymethyl-6-methyl-pyran-4(1H)-one. The preparation isachieved in one manufacturing process step. The amount of methanol iscritical for the success of the experiment, the preferred amount ofsolvent mixture is methanol and water in the ratio of 3:2.

The alcohol III is then oxidized to the acid (compound of formula Ifwherein R¹=Me, R⁴=H, R⁵=CH₂Ph) in a single process step. Jones reagent(chromium trioxide in sulfuric acid) converts the compound III to acidII in acetone, but the yield is extremely low and is less than 10%. Alarge amount of chromium waste is created. However, TEMPO, sodiumhypochlorite, baking soda and potassium bromide affords the acid in verygood yield, without chromatography and further recrystallization. Thereaction is carried out in an ice bath, with the internal reactiontemperature of less than 10° C. The reagents are extremely cheap and thereaction time is less than 24 hours. TEMPO is used in catalytic amount.

The acid II is converted to the amide I in one single process step. Theacid is reacted with 1,1′-carbonyldiimidazole in an inert solvent over aperiod of several hours. A solution of methylamine in alcohol is added.Elevation of the reaction temperature to between 60 to 100° C.,preferably 70 to 80° C. for a few hours, affords the amide (compound offormula I wherein R¹=Me, R²=Me, R³=Me, R⁶=H, R⁴=H, R⁵=CH₂Ph) in a singlemanufacturing step. The 3-benzyl alcohol protective group (compound offormula I wherein R⁵=CH₂Ph) can be removed by hydrogenation reaction orby acid. Procedures for the removal of protective group can be found inGreene, T. W., in Protective Groups in Organic Synthesis, John Wiley &Sons, 1981.

The starting materials required in this process are commerciallyavailable in kilogram to metric ton quantities. Allomaltol is preparedfrom the zinc reduction of 2-chlorokojic acid. The literature reportedthe use of excess thionyl chloride for the preparation of 2-chlorokojicacid. The reaction is heterogeneous and the procedure is not amenable tolarge scale synthesis and manufacture. However, 2-chlorokojic acid canbe prepared from kojic acid using 1 to 1.2 equivalent thionyl chloridein an inert solvent. The preferred inert solvent is acetonitrile and theproduct is easily isolated by filtration.

The above description details a general method for the conversion ofcompound III to II then to compound I.

The present invention will be more fully understood by the followingexamples which illustrate the invention, but are not considered limitingto the scope of the invention.

EXAMPLE 1 Preparation of Chlorokojic Acid

A 2-liter 3-neck round bottom flask was equipped with a mechanicalstirrer. The flask was charged with kojic acid (0.25 kg, 1.759 mol) and750 ml acetonitrile at 0° C. The kojic acid was insoluble inacetonitrile and stayed as a suspension. Thionyl chloride (140 ml, 1.919mol) was added dropwise via a dropping funnel at ice bath temperature.The solid slowly dissolved to give a red clear solution. After 15minutes, a white solid appeared. After 3 hrs at 0° C., the insolublesolid was filtered. The solid was filtered by suction filtration. Thesolid was mixed with water (0.5L) and then filtered. The acetonitrilemother liquor was reduced to 15% of the original volume and filtered.The solid was washed with water (200 ml) and then acetonitrile (50 ml).The combined solid was dried to constant weight (269 g, 95.2% yield).M.p. 166-1680° C. [lit value 166-167° C.]. 1H-NMR (DMSO-d₆) δ: 4.66 (s,2H, CH2Cl), 6.57 (s, 1H, CH), 8.12 (s, 1H, CH), 9.3 (br. s, 1H, OH).

EXAMPLE 2 Preparation of3-(Benzyloxy)-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one Procedure I

Allomaltol (Chem Abstract 1968-51-OP) was prepared from chlorokojic acidaccording to literature procedure published in J. Med. Chem., 1996, 39,3659-3670. Allomaltol (12.6g, 0.1 mol) was added to a solution of sodiumhydroxide (4.4 g, 0.11 mol) in water (60 ml). Formaldehyde (9 ml, 37%solution, 0.111 mol) was added dropwise at 0° C. The mixture was stirredat room temperature. A solid started to appear after 1.5 hr. Methanol(50 ml) was added and the mixture was left stirring for 16 hrs. Themixture was heated to 40° C. to effect dissolution of all insolublesolids. Benzyl chloride (12.65 ml, 0.109 mol), tetra-N-butylammoniumchloride (71 mg, 0.25 mmol) was added. The mixture was heated to refluxfor 3.5 hr. The solution was cooled and the pH of the solution droppedto pH=1. A solution of sodium hydroxide (2.5 g, 0.0625 mol) in water (10ml) was added. PhCH₂Cl (2 ml, 0.0173 mol) was added. The mixture washeated to reflux for 1.5 hr. The pH of the solution was at pH 12.5. Thesolution was cooled to room temperature. Methanol was removed byevaporation under reduced pressure. The mixture was cooled to 0° C. andextracted with dichloromethane (3×100 ml). The dichloromethane layer waswashed with brine, dried over sodium sulfate and evaporated to give ared oil. The oil was mixed with ethyl acetate (250 ml) and heated toeffect dissolution. The solution was cooled slowly with stirring to roomtemperature. A solid appeared. The mixture was cooled in an ice bath forone hr. The solid was isolated by filtration and dried to constantweight (14.5 gm). The mother liquor was evaporated to 15% of theoriginal volume. A solid was formed upon cooling to room temperature andthen 0° C. Suction filtration gave an additional 1.7 gm of the titledcompound. The total amount of solid isolated was 15.86 g (64.45% yield).H-NMR (CDCl₃)δ: 4.31 (s, 2H, CH₂OH), 5.21 (s, 2H, CH₂Ph), 6.21 (s, 1H,CH), 7.38 (br. s, 5H, Ph). M.p. 115-116° C. (lit. 114-116° C.).

EXAMPLE 3 Preparation of 3-(Benzyloxy)-6-methyl-4oxo-4H-pyran-2arboxylicacid Procedure I

A 1-liter 3-neck round bottom flask was equipped with a mechanicalstirrer and a dropping funnel. Dichloromethane (100 ml) was added to theflask followed by3-(benzyloxy)-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one (15.87 g, 0.064mol). Sodium bicarbonate solution (10%, 100 ml, 0.12 mol) was added,followed by solid sodium bicarbonate (13.5 g, 0.161 mol) and potassiumbromide (764 mg, 6.42 mmol). The mixture was cooled in an ice bath. Theinternal temperature of the reaction mixture was 3° C.

TEMPO (100 mg, 0.64 mmol) and tetra-n-butylammonium chloride hydrate(750 mg, 2.7 mmol) were added. Sodium hypochlorite solution (14.6%, 23ml, 0.045 mol, see note 3) was added dropwise, maintaining the reactiontemperature below 7° C. The addition of sodium hypochiorite solution(14.6%, 23 ml, 0.045 mol) took 25 minutes.¹ The pH of the top layer waschecked and measured a value of 9.0.

Sodium hypochlorite solution (14.6%, 25 ml, 0.049 mol) was addeddropwise¹ over a period of 60 minutes, maintaining the reactiontemperature below 7° C. Sodium bicarbonate solution (10%, 50 ml, 0.06mol) was then added and the pH of the solution was measured after 15minutes. At this time, the reaction mixture was white in color. The pHof the top layer was checked and had a value of pH 6.4.

Sodium hypochlorite solution (14.6%, 19 ml, 0.037 mol) was addeddropwise over 20 min, the pH of the upper layer was now at pH 7.4.2Sodium bicarbonate (13.5 g, 0.161 mol), TEMPO (60 mg, 0.384 mmol), KBr(700 mg, 5.88 mmol) was added, followed by dichloromethane (20 ml).Sodium hypochlorite (14.6%, 11.5 ml, 0.022 mol) was added dropwise overone hr, maintaining the reaction temperature below 7° C. TLC(EtOAc:hexane) showed that only a small amount of3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carbaldehyde was present. Thereaction mixture was filtered under suction. The filtrate wastransferred to a separatory funnel and the lower layer was returned tothe reaction vessel.

The upper layer was transferred to a round bottom flask and mixed with 1gm of sodium thiosulfate to destroy residual sodium hypochlorite. Thesolution was evaporated under reduced pressure for 5 minutes to removeresidual solvent. The solution was cooled in an ice bath and stirred.Concentrated hydrochloric acid was added dropwise until the solutionreached pH 1. A white precipitate appeared and was filtered after 1 hrat 0° C. The wet mass weighed 24 g.

The reaction vessel with the dichloromethane layer was mixed with sodiumbicarbonate solution (10%, 50 ml, 0.059 mol), sodium bicarbonate (13.5g, 0.161 mol), potassium bromide (700 mg, 5.88 mmol),tert-n-butylammonium chloride hydrate (500 mg, 1.8 mmol) andmechanically stirred. Sodium hypochlorite solution (14.6%, 14 ml, 0.0274mol) was added dropwise over a period of 1 hr. The mixture was stirredfor an additional 10 minutes and then the two layers were separated. Theupper layer was treated with sodium thiosulfate (1 gm) and then stirred.Concentrated hydrochloric acid was added dropwise until the solutionreached pH 1. A white precipitate appeared and was filtered after 1 hrat 0° C. The wet mass weighed 2 g.

The combined solid was washed with water and dried to constant weight(15.223 g, 91.1% yield). H-NMR (DMSO-d₆) δ:2.30 (s, 3H, Me), 5.10 (s,2H, PhCH₂), 7.35 (m, 2H, Ph), 7.43 (m, 2H, Ph). Mass spec: 261 (M+1).M.p. 173-174° C. [decomposition] (lit 173-175° C.).

Note¹: The solution turned yellow upon addition of the sodiumhypochlorite. Addition was stopped until the mixture turned white incolor. The addition of sodium hypochlorite was resumed and to maintainthe yellow color.

Note²: The pH of the reaction was measured with a pH meter.

Note³: Sodium hypochlorite solution was titrated before use. Thefollowing procedure is representative:

Sodium thiosulfate pentahydrate (12.405 g) was dissolved in water in a250 ml volumetric flask. The solution was diluted to 2.50 ml. Potassiumiodide (3 g) was suspended in 100 ml acetic acid in a 250 ml flask andstirred for 30 min at room temperature. The test sodium hypochloritesolution (2 ml) was pipetted into this mixture. A brown color was formedimmediately and the mixture was titrated against 0.2M sodium thiosulfatesolution from a buret until the solution turned colorless. The amount ofsolution required to the end point is Vs.

Therefore 0.5*0.2M*Vs=M_(NaOCl)*2 ml:

The molarity of the sodium hypochlorite solution M_(NaOCl) wascalculated.

Procedure II

A 500 ml round bottom flask was equipped with a stirrer and a droppingfunnel. Dichloromethane (15 ml) was added to the flask followed by3-(benzyloxy)-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one (3 g, 0.01233mol). Sodium bicarbonate (2.6 g, 0.031 mol) and potassium bromide (146mg, 0.001233 mol) and water (5 ml) was added. The mixture was cooled inan ice bath. The internal temperature of the reaction mixture was 3° C.

TEMPO (19.26 mg, 0.123 mmol) and tetra-n-butylammonium chloride hydrate(140.5 mg, 0.615 mmol) were added. Sodium hypochlorite solution (4.7%,25 ml, 0.0158 mol) was added dropwise, maintaining the reactiontemperature below 7° C. The addition took 30 minutes. The pH of thesolution dropped to 6.4. Sodium bicarbonate (4.3 g, 0.0512 mol) wasadded. The pH rose to 7.5.

Sodium hypochlorite solution (4.7%, 23 ml, 0.0145 mol) was addeddropwise over a period of 20 minutes, maintaining the reactiontemperature below 7° C. One drop of the solution was removed and testedwith a test tube containing potassium iodide (20 mg) in acetic acid (2ml). The solution turned yellow. This showed that very little excess ofsodium hypochlorite was present.

At 2.5 hr since the start of the experiment, the two phases wereseparated. The aqueous phase mixed with sodium thiosulfate (1 g) inwater (2 ml). The solution was evaporated for 5 minutes to removeresidual organic solvent and then acidified to pH 1 with stirring at 0°C. with dropwise addition of concentrated HCl. A white precipitateappeared and was filtered after cooling at 0° C. for 1 hr. The whitesolid was washed with water and then dried to constant weight (2.76 g,87% yield).

Procedure III

A 1-liter 3-neck round bottom flask was equipped with a mechanicalstirrer and a dropping funnel. Dichloromethane (300 ml) was added to theflask followed by3-(benzyloxy)-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one (63.48 g, 0.2574mol). Sodium bicarbonate solution (10%, 200 ml, 0.24 mol) was added,followed by solid sodium bicarbonate (54 g, 0.6428 mol) and potassiumbromide (3.06 g, 0.02574 mol). The mixture was cooled in an ice bath.The internal temperature of the reaction mixture was 3° C. TEMPO (400mg, 0.00256 mol) and tetra-n-butylammonium chloride hydrate (2.98 g,0.01287 mol) were added. Sodium hypochlorite solution (14.6%, 250 ml,0.49 mol) was added dropwise, maintaining the reaction temperature below7° C. The addition of sodium hypochlorite solution took 35 minutes. ThepH of the top layer was checked and measured a value of 8.0. Solidsodium bicarbonate (27 g, 0.321 mol) was added, followed by the dropwiseaddition of sodium hypochlorite solution (14.6%, 100 ml, 0.195 mol) overa period of 50 minutes at ice bath temperature. Solid sodium bicarbonate(20 g, 0.238 mol), 10% sodium bicarbonate solution (100 ml, 0.119 mol),potassium bromide (3 g, 0.0252 mol), and tetra-n-butylammonium chloridehydrate (2 g, 0.0087 mol) was added. Sodium hypochlorite solution(14.6%, 85 ml, 0.167 mol) was added dropwise over a period of two hrs.The pH of the solution dropped to 6.0. Solid sodium bicarbonate (16 g,0.190 mol) and potassium bromide (3 g, 0.025 mol) were added, followedby the dropwise addition of sodium hypochlorite solution (14.6%, 50 ml,0.098 mol) over 10 minutes. After 30 minutes of stirring at ice bathtemperature, the reaction mixture was filtered under suction. Thefiltrate was transferred to a separatory funnel. The upper layer wastransferred to a round bottom flask and mixed with 1 gm of sodiumthiosulfate to destroy residual sodium hypochlorite. The solution wasevaporated under reduced pressure for 5 minute to remove residualsolvent. The solution was cooled in an ice bath and stirred.Concentrated hydrochloric acid was added dropwise until the solutionreached pH 1. A white precipitate appeared and was filtered after 1 hrat 0° C. The solid was washed with water and dried to constant weight(49.04 g, 73% yield).

Procedure IV

A 250 ml round bottom flask was equipped with a stirrer and a droppingfunnel. Dichloromethane (5 ml) was added to the flask followed by3-(benzyloxy)-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one (1 g, 4.06mmol). Sodium bicarbonate (314 mg, 3.74 mol) and potassium bromide (96.5mg, 0.81 mmol) in water (2.5 ml) were added. The mixture was cooled inan ice bath. The internal temperature of the reaction mixture was 3° C.

TEMPO (6.4 mg, 0.041 mmol) was added. Sodium hypochlorite solution(4.7%, 7.5 ml, 4.73 mmol) was added dropwise, maintaining the reactiontemperature below 7° C. After 1.5 hr, TLC (EtOAc/hexane) showed all thestarting material has been converted to the3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carbaldehyde. At this time, themixture was red in color. An additional amount of sodium hypochloritesolution (4.7%, 6.5 ml, 4.1 mmol) was added dropwise at ice bathtemperature. The mixture was stirred at ice bath temperature for 1 hr.The two layers were separated. The aqueous layer was tested for excesshypochiorite. One drop of the solution was mixed with KI (20 mg) inacetic acid (2 ml). The solution turned yellow indicating that there wasvery little sodium hypochlorite left. The aqueous layer was evaporatedunder reduced pressure for 3 minutes to remove organic solvent. It wascooled in an ice bath and rapidly stirred. Conc. HCl was added until thepH reached 1. An insoluble white solid appeared and was isolated bysuction filtration. The material was washed with water and dried toconstant weight (800 mg). The dichloromethane layer from the extractionwas mixed a suspension of potassium bromide (84 mg, 0.71 mmol) andsodium bicarbonate (180 mg, 2.14 mmol) in water (3 ml) at ice bathtemperature. Sodium hypochlorite (4.7%, 3 ml, 1.89 mmol) was addeddropwise. After 1 hr, the two layers were separated, the aqueous phasewas extracted with dichloromethane (5 ml), and then evaporated to removeresidual organic solvent. The aqueous phase was acidified to pH 1 by thedropwise addition of conc. HCl at ice bath temperature. The insolublewhite solid was filtered and dried to constant weight (203 mg). Thecombined product (1.003 g) was isolated in 98.9% yield.

EXAMPLE 4 Preparation of3-(Benzyloxy)-N,1,6-trimethyl-4oxo-1,4-dihydropyridine-2-carboxamideProcedure I

1,1′-carbonyldiimidazole (3.2 g, 19.7 mmol) was added to a solution ofthe 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid (3.2 g, 12.3mmol) in DMF (25 ml) at room temperature. The resulting solution washeated at 45 to 50° C. for 3 hrs. A clear yellow solution was observed.A solution of methylamine in methanol (25 ml of 1M solution, 27.33 mmol)was added. The reaction mixture was stirred at 65 to 70° C. for 3 hrunder pressure in a sealed system. The reaction was cooled between 40 to50° C. at which time a solution of methylamine in methanol (20 ml of 1Msolution, 21.87 mmol) was added. The solution was stirred at 65 to 70°C. for 15 hrs under pressure. The solvent was removed under reducedpressure and dichloromethane was added (150 ml). The solution was washedwith water and dried over magnesium sulfate (2 g). Solvent evaporationgave a yellow oil that was passed through a short silica gel column (3″height by 1″ diameter). The column was eluted with 10% methanol in ethylacetate to give the titled compound (2.3 g, yield 66%). H-NMR (CDCl₃)δ:2.20 (s, 3H, Me), 2.68 (d, 3H, NHMe), 3.49 (s, 3H, NMe), 5.03 (s, 2H,PhCH₂), 6.14 (s, 1H, CH), 7.32 (m, 5H, Ph), 0.788 (br. s, 1H, NH). H-NMR(DMSO-d₆):2.28 (s, 3H, Me), 2.74 (d, 3H, NHMe), 3.42 (s, 3H, NMe), 5.05(s, 2H, PhCH₂), 6.20 (s, 1H, CH), 7.33 (m, 5H, Ph), 0.8.77 (br. s, 1H,NH). Mass spect. 287 (M+1). M.p. 187.5-188.5° C. (lit m.p. 164-165.5°C.: source p. 35, WO98/54138).

Procedure II

1,1′-carbonyldiimidazole (0.5 g, 3.07 mmol) was added to a solution ofthe

3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid (0.5 g, 1.92mmol) in DMF (25 ml) at room temperature. The resulting solution washeated at 45 to 50° C. for 2.5 hrs. A clear yellow solution wasobserved. A solution of methylamine in methanol (5 ml of 2M solution,0.01 mol) was added. The reaction mixture was stirred at 45 to 50° C.for 2.5 hrs, and then stirred at room temperature for 15 hrs. A solutionof methylamine in methanol (5 ml of 2M solution, 0.01 mol). The solutionwas stirred at 65 to 70° C. for 2 hrs in a sealed tube. The solvent wasremoved under reduced pressure and dichloromethane was added (50 ml).The solution was washed with water and dried over magnesium sulfate.Solvent evaporation gave a yellow oil, which was passed through a shortsilica gel column (3″ height by 1″ diameter). The column was eluted with10% methanol in ethyl acetate to give the titled compound (0.27 g, yield72%).

EXAMPLE 5 Preparation of3-(Benzyloxy)-N,N-diethyl-1,6-dimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide

1,1′-carbonyldiimidazole (1.87 g, 111.53 mmol) was added to a solutionof the 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid (2.0 g,7.69 mmol) in DMF (15 ml) at room temperature. The resulting solutionwas heated at 40° C. for 3 hrs. A clear yellow solution was observed.Diethylamine (1.08 ml, 9.2 mmol) was added. The reaction mixture wasstirred at 40 to 45° C. for 2 hrs. The reaction was cooled to roomtemperature at which time a solution of methylamine in methanol (11 mlof 2M solution in methanol, 15.4 mmol) was added. The solution wasstirred at 65 to 70° C. for 15 hrs under pressure. The solvent wasremoved under reduced pressure and dichloromethane was added (70 ml).The solution was washed with water and dried over magnesium sulfate (1g). Solvent evaporation gave light yellow oil as a crude product. Thecolumn was eluted with 10% to 25% methanol in ethyl acetate to give thetitled compound (1.74 g, yield 67%). H-NMR (CDCl₃) σ:1.09 (t, J=7.11 Hz,3H, Me), 1.16 (t, J=7.04 Hz 3H, Me), 2.34 (s, 3H, Me), 3.13-3.30 (m, 2H,CH₂), 3.47 (s, 3H, NMe), 3.50-3.60 (m, 2H, CH₂), 4.91(d, J=10.76 Hz, 1H,CH₂), 5.52(d, J=10.74 Hz, 1H, CH₂), 6.41 (s, 1H, CH), 7.10-7.33 (m, 5H,Ph), Mass spect. 329 (M+1).

EXAMPLE 6 Preparation ofN,N-diethyl-3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide

Pd(OH)₂ on charcoal (0.1 g) was added to a solution of3-(benzyloxy)-N,N-diethyl-1,6-dimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide(1.0g, 3.05 mmol) in ethanol (100 ml) under nitrogen. The mixture washydrogenated at 50 psi hydrogen for 4 hrs. The Pd(OH)₂ was removed byfiltration through Celite and the Celite cake was washed with ethanol(3×10 ml). The ethanol filtrate was evaporated to give a slightly redsolid (0.66 g, 94%). Melting point: 128 to 130° C. H-NMR (CDCl₃) σ:1.19(t, J=7.11 Hz, 3H, Me), 1.30 (t, J=7.00 Hz, 3H, Me), 2.36 (s, 3H, Me),3.36 (m, 2H, CH₂), 3.38 (s, 3H, NMe), 3.64 (q, J=6.90 Hz, 2H, CH₂), 6.35(s, 1H, CH), Mass spect. 239 (M+1).

EXAMPLE 7 Preparation of3-hydroxy-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide

Pd(OH)₂ on charcoal (0.2 g) was added to a solution of3-(benzyloxy)-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide(1.25 g, 4.366 mmol) in ethanol (120 ml) under nitrogen. The mixture washydrogenated at 50 psi hydrogen for 4 hrs. The Pd(OH)₂ was removed byfiltration through Celite and the Celite cake was washed with ethanol(3×25 ml). The Celite cake was further stirred with ethanol (100 ml) andthen filtered through Celite. The combined ethanol filtrate wasevaporated to give a solid (0.86 g, quantitative yield). Meltingpoint: >250° C. H-NMR (COCl₃:DMSO-d₆ [2:1]) δ:1.81 (s, 3H, Me), 2.34 (d,3H, NHMe), 3.01 (s, 3H, NMe), 5.67 (s, 1H, CH), 7.88 (s, 1H, NH).Elemental Analysis: Calc. C 55.09; H 6.6; N 14.28. Found. C 54.67; H6.31; N 14.12.

What is claimed is:
 1. A process for the preparation of a compound offormula I:

wherein: R¹, R², R³, R⁶ are, independently, hydrogen or a lower alkyl,R⁴ is a lower alkyl, hydrogen, or a lower alkoxy, R⁵ is hydrogen or analcohol protective group, comprising: (i) reacting a compound of formulaII:

 wherein R¹, R⁴, R⁵ are as defined above, with1,1′-carbonyldiimnidazole; (ii) reacting the mixture resulting from step(i) with a compound of formula  R³R⁶NH, wherein R³ and R⁶ are as definedabove, and (iii) reacting the mixture resulting from step (ii) withR²NH₂ so that said compound of formula I is produced.
 2. The process ofclaim 1 wherein: R¹, R² and R³ are methyl, R⁴ is hydrogen, R⁵ is benzyl,and R⁶ is hydrogen.
 3. The process of claim 1 wherein said alcoholprotective group is benzyl or a benzyl group substituted with nitro, alower alkyl or a lower alkoxy.